Approximately 400,000 coronary artery bypass graft (CABG) procedures are conducted annually in the United States. The frequency of the most debilitating problems (such as myocardial infarction, postoperative low cardiac output syndrome, and stroke) are estimated to be in the range of 5-10%, whereas modest cardiac dysfunction and cognitive disorders may have frequencies of 50-60%. Unfortunately it is difficult to obtain a precise fix on the frequency of heart and CNS related complications in surgeries with cardiopulmonary bypass because the definitions of "complications" vary and there may be a tendency to miss significant problems when they are assessed retrospectively rather than observed prospectively. Even if estimates as low as 5% are correct, this percentage represents 20,000 patients that will be able to benefit from improved protection during a CABG operation. A potentially more important factor that could influence the complication rates now and in the future may be the changing demographics of the surgical populations. Since patients undergoing CABG procedures are tending to be older and higher risk individuals as the general population ages, it appears likely that the frequency of serious complications will increase.
During CAGB operations, the heart and lungs are isolated from the rest of the circulatory system which is supported by a cardiopulmonary bypass pump. Hypothermia, cardioplegia and other means of protecting the heart or brain are used routinely in CABG procedures, but ischemia remains a significant and serious risk that can lead to myocardial infarction, prolonged postoperative dysfunction, stroke, or cognitive disorders.
Adenosine receptor activation is an important part of ischemic events. Swain et al., Circulation Research, 1982, 51:102-105; Holmes et al., U.S. Pat. No. 4,575,498 (issued Mar. 11, 1986); and Mitsos et al., Pharmacology, 1985, 31:121-131. Techniques that would increase extracellular levels of adenosine or adenosine analogs at specific times during a pathological event such as ischemia, that would increase these compounds without complex side effects, would therefore be of considerable therapeutic use. One reason for lower levels of adenosine has to do with the presence of the enzyme, adenosine deaminase, in the ischemic area.
Several methods exist for increasing the activation of adenosine receptors. One method is the systemic administration of adenosine. Unfortunately, the systemic administration of adenosine or adenosine analogs tends to reduce blood pressure and induce bradycardia. Therefore, another mechanism of increasing adenosine levels only in the ischemic area is necessary, this would permit increased adenosine levels to be selectively targeted to cells that would benefit most from them.
One alternate mechanism for increasing adenosine levels is to inhibit adenosine deaminase. U.S. Pat. No. 4,912,092 issued Mar. 27, 1990 to Gruber discloses methods for increasing extracellular concentrations of adenosine for the prophylactic or affirmative treatment of diseases of the cardiac and vascular systems involving administering to a patient purine nucleoside and purine nucleoside-related analogs which increase extracellular adenosine concentration. Examples of compounds useful in the invention include compounds broadly classified as purine nucleosides and related analogs, such as AICA riboside, in various pro-forms. The Gruber reference also discloses that pentostatin is a potent inhibitor of the enzyme adenosine deaminase that enhances the effect of the purine nucleoside in elevating adenosine concentrations for a bodily condition. One of the bodily conditions the compounds may be administered to include seizure activity, arrhythmias, or a condition resulting in decreased blood flow. The disclosure of the Gruber reference is hereby incorporated by reference.
World Patent Application 87/05807 to H. E. Gruber, claims a method of treating an animal body for diseases associated with restricted blood flow comprising the administration of purine nucleosides, which may be AICA riboside. The application also claims the use of 2'-deoxycoformycin to enhance the effect of said purine nucleosides. The application is related to U.S. Pat. No. 4,912,092 issued to H. E. Gruber on Mar. 27, 1990 which is discussed above.
U.S. Pat. No. 4,713,372 issued Dec. 15, 1987 to Schaumberg discloses the administration of pentostatin to inhibit adenosine deaminase in order to combat viruses. The patent does not disclose the use of pentostatin to prophylactically or affirmatively treat cerebral and cardiovascular disorders.
The literature contains reports on the effects of adenosine deaminase inhibitors which were used to enhance or maintain local adenosine levels in the heart and brain. For example, pentostatin and erythro-9 (2-hydroxy-3-nonyl) adenine (EHNA) improved functional and metabolic recovery after global ischemia in isolated rabbit (Bolling SF, Bies LE, Bore El, Gallagher KP, Augmenting intracellular adenosine improves myocardial recovery, J Thorac Cardiovasc Surg 99: 469-474, 1990) and rat hearts (Dhasmana JP, Digerness SB, Geckle JM, Ng TC, Glickson JD, Blackstone EH: Effect of adenosine deaminase inhibitors on the heart's functional and biochemical recovery from ischemia: A study utilizing the isolated rat heart adapted to 31-P nuclear magnetic resonance. J Cardiovasc Pharm 5: 1040-1047, 1983). In the brain, inhibition of adenosine deaminase lead to accumulation of interstitial adenosine in rats (Sciotti VM, Van Wylen DGL: Increases in interstitial adenosine and cerebral blood flow with inhibition of adenosine kinase and adenosine deaminase. J Cereb Blood Flow Metab 13: 201-207, 1993) and pentostatin (0.5 mg/kg, corresponding approximately to 3.0 mg/m.sup.2 in humans) has been demonstrated to have beneficial effects in rat and gerbil models of cerebral ischemia or hypoxia (Phillis JW, O'Regan MH, Walter GA: Effects of deoxycoformycin on adenosine, inosine, hypoxanthine, xanthine, and uric acid release from the hypoxemic rat cerebral cortex. J Cereb Blood Flow Metab 8: 733-741, 1988; Phillis JW, O'Regan MH: Deoxycoformycin antagonizes ischemia-induced neuronal degeneration. Brain Res Bull 22: 537- 540, 1989; Phillis JW, Walter GA, Simpson RE: Brain adenosine and transmitter amino acid release from the ischemic rat cerebral cortex: Effects of the adenosine deaminase inhibitor deoxycoformycin. J Neurochem 56: 644-650, 1991). In one report, however, in rat model of transient forebrain ischemia, no beneficial effects of pentostatin were observed (Delaney SM, Sutherland GR, Peeling J, Geiger JD: Failure of 2'-deoxycoformycin to protect against transient forebrain ischemia in rat. Neuroscience Letters 149: 31-34, 1993).
[R]-3-(2-deoxy-.beta.-D-erythropentofuranosyl)-3,6,7,8-tetrahydroimidazo[4, 5-d][1,3]diazepin-8-ol, 2'-deoxycoformycin or pentostatin, is described in U.S. Pat. No. 3,923,785. The compound is disclosed there as having in vitro and in vivo activity against DNA viruses such as herpes and vaccinia. A method for purifying pentostatin is disclosed in copending U.S. application Ser. No. 07/738,715 filed Jul. 31, 1991. The patent and patent application are hereby incorporated by reference.
There is no disclosure in the above references to suggest the methods of the present invention for increasing extracellular adenosine concentration to allow adenosine receptor activation in ischemic areas, thus treating cerebral and cardiovascular disorders such as myocardial and cerebral ischemia.